Diseases caused by viruses (viral infections) are widespread throughout the world and constitute a serious problem in medicine, in particular because of the high variability, adaptability and mutation rate of viruses. Viruses are small particles of approximately 15 to 400 nm, which are unable to replicate themselves but instead require a host cell to do so. Depending on their host specificity, viruses are differentiated according to those which attack animals (invertebrates and vertebrates), plants, bacteria or algae, fungi and protozoa. Viral infections are characterized in general by a high replication rate of the viral particles in the infected host cells, which can be described with an exponential law. The general reproduction cycle of viruses takes place via injection of their nucleic acid (RNA or DNA) into the host cell, in which the replication of the nucleic acid takes place by utilizing the replication apparatus of the host cell. Replication of viruses may take place either in the lytic or lysogenic cycle. In the lytic cycle (active infection), the viral nucleic acid is replicated in the cell nucleus of the host cell after injection of the nucleic acid, the new viral particles are assembled in the cytoplasm, whereupon the host cell is ultimately lysed (destroyed) and the viruses are released. Viruses released in this way then infect other host cells. In the lysogenic cycle, the nucleic acid (DNA) of the virus is integrated into the genome of the host cell, where it remains without destroying the host cell. This lysogenic cycle may be converted to a lytic cycle as described above due to external influences (e.g., UV radiation, addition of mutagenic substances).
Virus-based diseases of the skin are understood in general to be diseases of the skin caused by a virus. Virus-based diseases of the skin include in particular diseases and/or infections which are caused by herpesviruses and are also referred to colloquially simply as herpes. Herpesviruses occur widely in vertebrates, in particular in mammals and especially in humans, horses, swine, cattle, goats, sheep, cats and dogs.
Human pathogenic herpesviruses (HHV) are differentiated according to alpha, beta, and gamma-herpesviruses (HHV-1 through HHV-8), where the alpha and gamma viruses are also among viruses that can infect animals, e.g., the horse (equine herpesvirus), cattle (bovine herpesvirus), swine (porcine herpesvirus), cat (feline herpesvirus), dog (canine herpesvirus) and chicken (chicken herpesvirus 1).
Of the human pathogenic herpesviruses, those which infect humans, in particular the alpha-herpesviruses, are of great importance. The alpha-herpesviruses include herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) and varicella zoster virus (VZV).
The diseases of the skin caused by herpes simplex viruses HSV-1 and HSV-2 include, for example, herpes labiales, also known as fever blisters or herpes of the lips, and herpes nasalis, both caused primarily by HSV-1, keratoconjunctivitis herpetica, stomatitis herpetica, herpes facialis, herpes buccalis, herpes genitales, herpes perianalis, herpes glutealis. Varicella zoster viruses (VZV) cause chickenpox and shingles, for example.
Virologists have estimated that 80% of the population worldwide has latent HSV-1 infections and 30% HSV-2. HSV-1 and HSV-2 are closely related to one another and have a high percentage of identical nucleotide sequences. Although HSV-1 infects primarily the oral and facial area, HSV-2 occurs mainly in the genital area.
Alpha-herpesviruses usually first infect epithelial cells such as skin cells, mucous cells and mucosal cells, followed by a marked replication of the virus in the host cell and death of the infected host cell.
For example, HSV-1 will spread in skin cells and/or mucosal cells of the face and mouth, usually causing local damage, namely in the form of a vesicle. Antibodies neutralize the viruses in the vesicles after a short period of time, but viruses are also released by lysis of the infected host cells before a humoral immune response can take place. The viruses thereby released also infect certain nerve cells (neurons) by adhering to receptors on the nerve endings in the mouth, which can lead to the neural node of the facial nerve (trigeminus). The viral DNA penetrates into an axon, enters the cytoplasm of the nerve cells and finally enters the cell nucleus where the viral DNA is incorporated into the genome of the nerve cell, leading to a latency in which only a few viral genes are expressed (lysogenic cycle). Various external stimuli can be lead to renewed activation of the virus, i.e., the transition from latency and/or the lysogenic cycle to the lytic cycle which ultimately results in destruction (lysis) of the nerve cell. Such stimuli include, for example, immunosuppression, stress, hormone fluctuations, physical or emotional stresses, fever (which is also why they are called fever blisters), UV radiation, tissue damage and in many cases an immunological weakness. The incidence of such activation of HSV-1 probably depends on both genetic and environmental factors, and both age and hormone changes can play a role. The viral progeny occurring as part of an activation are first transported by the axon to the site and/or the region of the original skin infection where they again create vesicles or blisters (fever blisters) by infection of and replication in the skin cells and/or mucosal cells. Even if these viruses are again neutralized by the immune system, it is impossible to free the body completely of HSV-1 through the immune system because additional nerve cells in which the viral DNA remains integrated into the genome (latency) are constantly being infected.
Additional virus-based diseases of the skin, which are widespread, include diseases and/or infections which are caused by verrucal viruses and are referred to colloquially as warts.
Warts (verrucae) are small, flat or slightly raised, sharply delineated and highly contagious (under some circumstances) but usually benign epithelial tumors and/or proliferations of skin, in particular epidermis. They occur on the hands and feet in particular. Warts usually have a thick, horny, partially fissured coating of squamous epithelial cells beneath which there are soft tissue of keratinocytes.
These diseases of the skin (warts) are caused by a virus infection, mainly by papillomaviruses, in particular human papillomaviruses (HPV) such as verrucae vulgares, verrucae planae juvenilis, verrucae plantares, condylomata acuminata, verrucae planae, verrucae filiformes and molluscipox viruses, e.g., molluscum contagiosum. The infection occurs through small injuries in the skin and/or mucosa. Verruca viruses infect skin cells of vertebrates, in particular mammals and especially humans.
Warts are fundamentally benign proliferations which may cause severe pain in certain areas, e.g., in the genital area and may in extremely rare cases develop into a malignancy. They may also become a cosmetic problem due to their appearance and frequent further propagation on the skin. Treatment of warts is very tedious. So far various therapeutic approaches have been developed:
Surgical removal                Electrocoagulation        Laser removal        Cryosurgery (freezing)        Cauterization (use of electric current or caustic agents)        Cytostatics such as 5-fluorouracil, podophyllotoxin and podophylline which are painted on the warts.        
All the therapeutic approaches listed above are, however, based on treatment of the sequelae of a verrucal virus infection, not on inhibition or prevention of viral replication.
In contrast with that, the herpesvirus-based diseases of the skin mentioned above are generally treated by using antiviral active ingredients which intervene in viral replication in particular. This will be discussed in greater detail below.
An important general approach in the development of antiviral active ingredients and thus also in the prevention and/or treatment of virus-based diseases of the skin is thus to intervene in the viral replication cycle and to inhibit viral infection of the host cell or replication of the viral nucleic acid in the host cell, e.g., by inhibiting expression of the viral proteins coded by the viral nucleic acid.
In recent decades, such antiviral active ingredients, so-called virustatics have been developed. Many virustatics inhibit the enzyme DNA polymerase, reverse transcriptase or proteases, for example, and thus inhibit replication of the virus and/or processing of a synthesized long virus protein into smaller protein segments. Examples of these therapeutic approaches are to be found here in particular in the treatment of HIV infections. However, virustatics that are administered systemically or topically are also known in the field of treatment of virus-based diseases of the skin caused by herpesviruses HSV-1 or HSV-2. Examples include the active ingredients aciclovir, valaciclovir, foscarnet and peniclovir.
In general two approaches are known for prevent and/or treatment of virus-based diseases of the skin with virustatics:                (1) systemic administration: by systemic administration of virustatics, a significant reduction in the activation of viruses present in host cells can be achieved because the active ingredients inhibit the replication of the viral nucleic acid in the cell nucleus or the assembly of the viral particles to form complete viruses in the cytoplasm of the host cells;        (2) topical administration: by topical administration of virustatics in the area of an initial infection by the virus, the additional route of replication of the viruses, e.g., in the resulting fever blisters in the case of an HSV-1 infection, can be prevented in an early stage of activation, which can result in more rapid detumescence of the fever blisters.        
Both approaches have some important disadvantages for administration of virustatics:                In systemic administration, the dose required for effective treatment is relatively high and is associated with serious adverse effects for the organism thereby treated such as, for example, nonspecific immune responses and autoimmune responses. In the case of aciclovir, numerous such adverse effects are known from the literature. Therefore, neither long-term treatment nor repeat treatment is advisable nor can it be expected of a patient.        In topical administration, the amount of active ingredient (virustatic) that can be released and be bioavailable per unit of time in the area of the virus infection, e.g., the fever blister is very low. This low bioavailability of the virustatic is an important obstacle for effective topical treatment. In the case of aciclovir which has a very low water solubility, the low bioavailability is due to the poor percutaneous transport of the active ingredient, for example. Various chemical modifications of virustatics as prodrug concepts for an improved supply of virustatic active ingredient have not led to any improvement in this phenomenon.        
Of the virustatics described in the literature for treatment of virus-based diseases of the skin, aciclovir which has already been mentioned is described as one of the most effective virustatics for which there are almost no alternatives.
There are alternatives to the known antiviral active ingredients, in particular the virustatics, for prevention and/or treatment for virus-based diseases of the skin, which overcome the disadvantages known in the state of the art. There is therefore a need for developing improved and better tolerated antiviral active ingredients, which will intervene in the replication cycle of the virus and preferably inhibit (i.e., prevent) viral infection of the host cell and replication of the viral nucleic acid in the host cell.